PROJECT SUMMARY ?lpha-1 antitrypsin (AAT) deficiency (AATD) and Chronic Obstructive Pulmonary Disease (COPD) are lung diseases, both of which share phenotypic features, including airflow obstruction and airway mucociliary dysfunction, attributed primarily to emphysema, a condition that defines damage and enlargement of the air sacs of the lungs, causing breathlessness . AATD is the major genetic cause of early-onset COPD, typically exacerbated by cigarette smoking. There is still no cure for AATD/COPD-associated emphysema; no treatment can reverse the damage to the lungs. Prevalence of COPD is increasing significantly, warranting need for new therapies. Lack of a proper animal model that mimics the human disease has been a constraint, owing to structural and functional differences between human and rodent lungs. We propose that pigs with a genetic model of emphysema, in conjunction with exposure to cigarette smoke (CS) could provide consistent pulmonary tissue alterations that are characteristic features of AATD/COPD. This swine model will be of great value for pre-clinical research and facilitate development of innovative treatments to slow, stop or reverse the damage to the lungs caused by AATD/COPD. For that, we plan to generate pigs with AATD, the only defined, genetic risk factor of emphysema. AATD is caused by a mutation of the protease inhibitor (PI) gene, resulting in a reduced level of AAT in blood and lung, leading to breakdown of the lung tissue by the enzyme neutrophil elastase. We intend to utilize our novel gene-editing platform to develop swine with the most prevalent and severe AATD genotype, PI*ZZ. Accordingly, the pig model with the PI*ZZ mutant genotype will develop emphysema, a characteristic feature of AATD PI*ZZ mutant genotype will be exposed to CS to intensify the AATD phenotype to COPD. PI*ZZ . Then, this Realization of this mutant genotype will be monitored by serological testing in vivo, while progression of emphysema is evaluated clinically and confirmed pathomorphlogically. We believe that such a reliable large animal model of AATD/COPD- linked emphysema will have tremendous impact on industry and academic research to develop and test new drugs and novel therapeutic approaches to treat AATD/COPD-associated emphysema.